U.S. Pat. No. 4,703,053, which is herein incorporated by reference, discloses novel benzothiophene and benzofuran derivatives having antiallergy activity.
Connor D. T., et al., J. of Medicinal Chemistry, 35:958-965 (1992) discloses a series of novel benzothiophene, benzofuran, and naphthalenecarboxamidotetrazoles as antiallergy agents.
Particularly valuable as an antiallergic agent is 5-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-yl-benzo[b]thiophene-2-carbox amide, sodium salt. This compound has also been shown to be useful as an antiasthmatic and gastric cytoprotective as well as an agent for treating rhinitis and inflammatory bowel disease.
5-Methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid is a key intermediate in the preparation of 5-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-yl-benzo[b]thiophene-2-carbox amide, sodium salt. This key intermediate, in turn, is prepared as disclosed in U.S. Pat. No. 4,703,053 in seven steps from 5-methoxysalicylic acid.
U.S. Pat. No. 4,910,317 and 4,931,459 disclose novel benzothiophene and benzofuran derivatives having antiallergy activity. Benzo[b]-thiophene-2-carboxylic acids, which are key intermediates for preparing these compounds, are prepared from 3-chlorobenzo[b]thiophene-2-carbonyl chlorides. The previous acid chlorides, in turn, are prepared from cinnamic acids using methodology disclosed by Wright W. B., Jr. and Brabander H. J., J. of Heterocyclic Chemistry, 8:711-714 (1971) and Pakray S. and Castle R. N., J. of Heterocyclic Chemistry, 23:1571-1577 (1986). Thus, the appropriate cinnamic acid is converted to a 3-chlorobenzo[b]thiophene-2-carbonyl chloride using thionyl chloride and pyridine. However, the yields of acid chloride are low and the procedure is difficult to conduct on a large scale.
We have surprisingly and unexpectedly found an improved procedure in which a cinnamic acid can be converted to a 3-chlorobenzo[b]thiophene-2-carbonyl chloride with thionyl chloride and 4-dimethylaminopyridine (DMAP). The process is general and affords high yields of the 3-chlorobenzo[b]thiophene-2-carbonyl chlorides. Additionally, the present process affords significant advantages compared to the previous procedures that make it amenable to a large-scale industrial synthesis. Thus, the DMAP is charged as a solid together with the cinnamic acid, thereby eliminating the slow "metering-in" of liquid pyridine. Also, the DMAP process is far more robust compared to the previous procedures. The pyridine process is very time dependent requiring close monitoring of the reaction. Extended reaction times cause significant yield reductions. Extended reaction times of 8 hours or more in the DMAP process do not cause any significant reductions in yields or purities. Furthermore, DMAP hydrochloride is filtered as a solid after extraction of the reaction mixture with a solvent, thereby eliminating previous hot extraction of the molten pyridinium hydrochloride layer with an organic solvent. The recovered DMAP hydrochloride may be reused directly in subsequent reactions without detriment to the chemical yield or purity. Finally, solid DMAP hydrochloride poses fewer waste disposal problems than the molten pyridinium hydrochloride from the pyridine process. DMAP hydrochloride is water soluble and is dissolved by recirculating water through the filter before disposal, in contrast to the slow quench of the molten layer into water.
The object of the present invention is an improved, efficient, environmentally safe and economical process for the preparation of 3-chlorobenzo[b]thiophene-2-carbonyl chlorides. Additionally, a second object of the present invention is an improved, efficient, and economical process for the preparation of 5-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-yl-benzo[b]thiophene-2-carbox amide, sodium salt.